It has been clear for several decades that elevated blood cholesterol is a major risk factor for coronary heart disease (CHD), and many studies have shown that the risk of CHD events can be reduced by lipid-lowering therapy. Prior to 1987, the lipid-lowering armamentarium was limited essentially to diet modification to a low saturated fat and cholesterol diet, the bile acid sequestrants (cholestyramine and colestipol), nicotinic acid (niacin), the fibrates and probucol. Unfortunately, all of these treatments have limited efficacy or tolerability, or both. With the introduction of lovastatin (MEVACOR®; see U.S. Pat. No. 4,231,938)—the first inhibitor of HMG-CoA reductase to become available for prescription in 1987—physicians for the first time were able to obtain comparatively large reductions in plasma cholesterol with very few adverse effects.
The HMG CoA reductase inhibitors, commonly known are statins, are divided into two groups: fermentation-derived and synthetic. In addition to the natural product lovastatin, there have been several semi-synthetic and totally synthetic HMG-CoA reductase inhibitors approved for prescription use, including simvastatin (ZOCOR®; see U.S. Pat. No. 4,444,784), pravastatin sodium salt (PRAVACHOL®; see U.S. Pat. No. 4,346,227), fluvastatin sodium salt (LESCOL®; see U.S. Pat. No. 5,354,772), atorvastatin calcium salt (LIPITOR®; see U.S. Pat. No. 5,273,995) and cerivastatin sodium salt (BAYCOL®; see U.S. Pat. No. 5,177,080). Still other HMG-CoA reductase inhibitors are known to be in development, for example pitavastatin also referred to as NK-104 (see PCT international publication number WO 97/23200); and rosuvastatin also known as ZD-4522 (CRESTOR®; see U.S. Pat. No. 5,260,440, and Drugs of the Future, 1999, 24(5), pp. 511-513). The structural formulas of these and additional HMG-CoA reductase inhibitors, are described at page 87 of M. Yalpani, “Cholesterol Lowering Drugs”, Chemistry & Industry, pp. 85-89 (5 Feb. 1996). The HMG-CoA reductase inhibitors described above belong to a structural class of compounds which contain a moiety which can exist as either a 3-hydroxy lactone ring or as the corresponding ring opened dihydroxy open-acid, and are often referred to as “statins.”
U.S. Pat. No. 5,356,896 describes a pharmaceutical dosage form comprising an HMG-CoA reductase inhibitor compound, e.g., fluvastatin sodium, which is stabilized against pH-related degradation by an alkaline stabilizing medium capable of imparting a pH of at least 8 to an aqueous solution or dispersion of the composition. The '896 patent states that the drug substance and the alkaline medium must be brought into intimate contacting association, preferably with an aqueous or other solvent-based preparative process, whereby “the drug substance and alkaline medium are blended together in the presence of minor amounts of, e.g., water, to provide particles containing the drug and alkaline substance in intimate admixture.” The resulting particles are dried and then are blended with filler and remaining excipients, which were set aside to comprise an “external phase” of said particles, to result in a composition suitable for encapsulation, tableting or the like.
In another embodiment described in the '896 patent, a solvent-based process is utilized to assist subsequent drying in a fluidized bed, whereby the drug substance and alkaline medium are wet granulated by known techniques, i.e. blended in the moistened state, together with an amount of the filler material and the resulting granules, after drying, are combined with any remaining filler and other set-asides, e.g., binder, lubricant, and can therefore be tableted, encapsulated, or otherwise shaped into a dosage form.
The '896 patent states that to achieve extended shelf life of the compositions, it is important “that the particles prepared by trituration or wet granulation or other aqueous-based process be substantially completely dried, i.e. to a weight loss on drying (L.O.D.) of not greater than 3%, and preferably not greater than 2%.” The '896 patent also describes conventionally performed drying by tray drying or in a fluidized bed, preferably the latter with drying typically performed at about 50.degree C. inlet temperature, and below 50% RH. The '896 patent additionally describes an alternative preparative procedure to the above-described trituration or wet granulation techniques, wherein the drug substance and the alkaline stabilizing medium can be co-lyophilized, i.e. freeze-dried, from aqueous solution as a step in situ of the drug manufacturing process.
Most statins are relatively insoluble, and are considered by those skilled in the art to be unstable in solution, and therefore this class of drugs is manufactured in solid form. However, there are those patients who can not ingest, digest, or otherwise take medications orally and there is a need for the administration of medications intravenously. There are clinical indications that statins through anti-inflammatory and possibly other mechanisms can reduce the incidence of heart attacks, strokes, as well as other inflammatory mediated conditions.